Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells

Abstract

TGF-beta activators and TGF-beta production stimulators are employed to maintain or increase vessel lumen diameter in a diseased or injured vessel of a mammal. Conditions such as restenosis following angioplasty, vascular bypass grafts, transplanted organs, atherosclerosis or hypertension are characterized by a reduced vessel lumen diameter. In a preferred embodiment of the invention, TGF-beta activators and production stimulators inhibit abnormal proliferation of smooth muscle cells. TGF-beta activators or production stimulators that are not characterized by an undesirable systemic toxicity profile at a prophylactic dose are also amenable to chronic use for prophylactic purposes with respect to disease states involving proliferation and/or migration of vascular smooth muscle cells over time. Further provided is a method for determining TGF-beta in vitro, thereby identifying a patient at risk for atherosclerosis and monitoring a recipient that has received one or more administrations of a TGF-beta activator or production stimulator.

What is claimed is: 
     
       1. A method for preventing atherosclerosis in a mammal at risk therefor, or treating atherosclerosis in a mammal, which method comprises orally administering to the mammal the following: a dose of a therapeutic agent in an amount effective when administered orally to elevate the level of TGF-beta, wherein the increase in TGF-beta inhibits atherosclerotic lesion formation or development in the mammal.   
     
     
       2. The method of claim 1 wherein a series of doses are administered. 
     
     
       3. The method of claim 1 wherein the therapeutic agent inhibits lipid accumulation by the vessel. 
     
     
       4. The method of claim 1 wherein the therapeutic agent comprises trans-2- 4-(1,2-diphenyl-1-butenyl)phenoxy!-N,N-dimethyl-ethylamine, or a structural analog thereof. 
     
     
       5. The method of claim 4 wherein the therapeutic agent comprises a structural analog of trans-2- 4-(1,2-diphenyl-1-butenyl)phenoxy!-N,N-dimethyl-ethylamine. 
     
     
       6. The method of claim 1 wherein the therapeutic agent stabilizes atherosclerotic plaque. 
     
     
       7. The method of claim 1 wherein the therapeutic agent stimulates the production of TGF-beta mRNA or the expression of TGF-beta. 
     
     
       8. The method of claim 1 wherein the therapeutic agent cleaves the propeptide form of TGF-beta. 
     
     
       9. A therapeutic method comprising orally administering to a mammal an amount of a therapeutic agent effective upon oral administration to elevate the level of TGF-beta so as to treat a diseased blood vessel in said mammal, wherein said disease is associated with the diminution in the lumen volume of the diseased vessel, and wherein the therapeutic agent stabilizes atherosclerotic plaque, inhibits lipid accumulation, or inhibits or reduces diminution in vessel lumen diameter in the diseased vessel. 
     
     
       10. The method of claim 9 wherein a series of doses is administered over time to the mammal. 
     
     
       11. The method of claim 9 wherein the therapeutic agent comprises trans-2- 4-(1,2-diphenyl-1-butenyl)phenoxy!-N,N-dimethyl-ethylamine, or a structural analog thereof. 
     
     
       12. The method of claim 9 wherein the therapeutic agent stimulates the production of TGF-beta mRNA or the expression of TGF-beta. 
     
     
       13. The method of claim 9 wherein the therapeutic agent cleaves the propeptide form of the TGF-beta. 
     
     
       14. The method of claim 1 or 9 wherein the therapeutic agent increases the bioavailability of TGF-beta. 
     
     
       15. The method of claim 1 or 9 wherein the administration increases the level of active TGF-beta in said mammal relative to the level of active TGF-beta in said mammal prior to said administration. 
     
     
       16. The method of claim 1 or 9 wherein the administration increases the level of latent TGF-beta in said mammal relative to the level of latent TGF-beta in said mammal prior to said administration.